1. Field of the Invention
This invention relates to a method of reducing mortality and morbidity after myocardial infarction in diabetic patients.
2. Background Information
Morbidity and mortality from cardiovascular disease is higher in patients with manifest diabetes or impaired glucose tolerance compared to patients without those disorders. Diabetics account for up to 24% of the total number of patients admitted to coronary care units for suspect infarction, whereas they constitute only about 5% of the general population [Malmberg and Ryden; Fuller J. H., Diabet. Metab. 19:96-99 (1993)]. In-hospital. mortality of diabetic patients with myocardial infarction is twice that of non-diabetics [Hamsten A., et al., J. Int. Med. 736:1-3 (1994) 236 Suppl.; Malmberg K. and Ryden L., Eur. Heart J. 9:256-264 (1988)]. Diabetics experience more morbidity and die more often in the post-acute recovery phase, mostly due to fatal re-infarction and congestive heart failure [Malmberg and Ryden; Stone P., et al., J. Am. Coll. Cardiol. 14:49-57 (1989); Karlson B. W., et al., Diabet. Med. 10(5):449-54 (1993); Barbash G. I., et al., J. Am. Coll. Cardiol. 22:707-713 (1993)]. The difference in mortality and morbidity between diabetics and non-diabetics following myocardial infarction persists, despite reduction in the incidence of morbidity and mortality following acute myocardial infarction [Granger C. B., et al., J. Am. Coll. Cardiol., 21(4):920-5 (1993); Grines C., et al., N. Engl. J. Med. 328:673-679 (1993)].
Factors responsible for the poor prognosis among diabetic patients with acute myocardial infarction may act before, during, or after the acute event. They include diffuse coronary atheromatosis, with more advanced and widespread coronary artery disease, which, together with a possible diabetic cardiomyopathy, may contribute to a high prevalence of congestive heart failure. Autonomic neuropathy with impaired pain perception and increased resting heart rate variability may also be of importance. A coronary thrombus is an essential part of an evolving infarction, and notably, platelet activity, coagulation, and fibrinolytic functions have been found to be disturbed in diabetic patients [Davi G., et al., New England. J. Med., 322:1769-1774 (1990)].
Exaggerated metabolic disturbances in diabetics may play an important role. Myocardial infarction causes a reduction in circulating insulin, a dramatic increase in adrenergic tone, and the release of stress hormones, such as, cortisone, catecholamines, and glucagon, that together enhance hyperglycemia and stimulate lipolysis. The released free fatty acids further injure the myocardium via several mechanisms, and excessive oxidation of free fatty acids may possibly damage nonischemic parts of the myocardium [Rodrigues B., et al., Cardiovascular Research, 26(10):913-922 (1992)].
Palliative measures to normalize blood glucose and to control the metabolic cascade that exacerbates infarct damage in diabetics are needed. In a recent trial, improved metabolic care of diabetic patients during acute myocardial infarction, including carefully-monitored infusion of insulin and glucose, and post-acute tight regulation of blood glucose by subcutaneous multidose insulin treatment lowered mortality during the year following myocardial infarction by 30% compared with a control group of diabetics who did not receive insulin treatment unless deemed clinically necessary [Malmberg, K, et al., J. Am. College Cardiology, 26:57-65 (1995)].
Insulin infusion, however, creates the potential for hypoglycemia, which is defined as blood glucose below 0.3 mM. Hypoglycemia increases the risk of ventricular arrhythmia and is a dangerous consequence of insulin infusion. An algorithm for insulin infusion for diabetics with myocardial infarction was developed to prevent hypoglycemia [Hendra, T. J., et al., Diabetes Res. Clin. Pract., 16:213-220 (1992)]. However, 21% of the patients developed hypoglycemia under this algorithm. In another study of glucose control following myocardial infarction, 18% of the patients developed hypoglycemia when infused with insulin and glucose [Malmberg, K. A., et al., Diabetes Care, 17:1007-1014 (1994)].
Insulin infusion also requires frequent monitoring of blood glucose levels so that the onset of hypoglycemia can be detected and remedied as soon as possible. In patients receiving insulin infusion in the cited study [Malmberg, 1994], blood glucose was measured at least every second hour, and the rate of infusion adjusted accordingly. Thus, the safety and efficacy of insulin-glucose infusion therapy for myocardial infarct patients depends on easy and rapid access to blood glucose data. Such an intense need for monitoring blood glucose places a heavy burden on health care professionals, and increases the inconvenience and cost of treatment. As a result, cardiac intensive care units often do not allot resources for optimizing blood glucose levels in diabetics with acute myocardial infarction, as might be obtained by intravenous administration of insulin. Considering the risks and burdens inherent in insulin infusion, an alternate approach to management of blood glucose during acute myocardial infarction in diabetics is needed.
The incretin hormone, glucagon-like peptide 1, abbreviated as GLP-1, is processed from proglucagon in the gut and enhances nutrient-induced insulin release [Krcymann B., et al., Lancet 2:1300-1303 (1987)]. Various truncated forms of GLP-1, are known to stimulate insulin secretion (insulinotropic action) and cAMP formation [see, e g., Mojsov, S., Int. J. Peptide Protein Research, 40:333-343 (1992)]. A relationship between various in vitro laboratory experiments and mammalian, especially human, insulinotropic responses to exogenous administration of GLP-1, GLP-1(7-36) amide, and GLP-1(7-37) acid has been established [see, e.g., Nauck, M. A., et al., Diabetologia, 36:741-744 (1993); Gutniak, M., et al., New England J. of Medicine, 326(20):1316-1322 (1992); Nauck, M. A., et al., J. Clin. Invest., 91:301-307 (1993); and Thorens, B., et al., Diabetes, 42:1219-1225 (1993)]. GLP-1(7-36) amide exerts a pronounced antidiabetogenic effect in insulin-dependent diabetics by stimulating insulin sensitivity and by enhancing glucose-induced insulin release at physiological concentrations [Gutniak M., et al., New England J. Med. 326:1316-1322 (1992)]. When administered to non-insulin dependent diabetics, GLP-1(7-36) amide stimulates insulin release, lowers glucagon secretion, inhibits gastric emptying and enhances glucose utilization [Nauck, 1993; Gutniak, 1992; Nauck, 1993].
The use of GLP-1 type molecules for prolonged therapy of diabetes has been obstructed because the serum half-life of such peptides is quite short. For example, GLP-1(7-37) has a serum half-life of only 3 to 5 minutes. GLP-1(7-36) amide has a half-life of about 50 minutes when administered subcutaneously. Thus, these GLP molecules must be administered as a continuous infusion to achieve a prolonged effect [Gutniak M., et al., Diabetes Care 17:1039-1044 (1994)]. In the present invention, GLP-1's short half-life and the consequent need for continuous administration are not disadvantages because the patient is typically bed-ridden, in a cardiac intensive care unit, where fluids are continuously administered parenterally.